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Background: Type 2 diabetes mellitus (T2DM) often progresses to require basal insulin therapy. Despite the efficacy of once-daily basal insulins such as glargine and degludec, daily injections remain a barrier to adherence. Insulin efsitora alfa, a novel once-weekly fragment crystallizable (Fc)-fusion basal insulin, may improve treatment convenience while maintaining glycemic control. Objective: To evaluate the efficacy and safety of once-weekly insulin efsitora alfa compared with once-daily basal insulin analogs in adults with T2DM. Methods: An updated systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420251118205). PubMed, Embase, and CENTRAL were searched up to 30 July 2025 for randomized controlled trials (RCTs) comparing insulin efsitora alfa with once-daily basal insulins. Pooled analyses were performed using a random-effects model in RevMan 5.4. Risk of bias was assessed with the Cochrane RoB-2 tool, and evidence certainty with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: Six RCTs comprising 4115 participants were included. Once-weekly insulin efsitora showed non-inferior HbA1c reduction compared with daily basal insulin (mean difference = −0.04; 95% confidence interval: –0.13 to 0.05; P = 0.35). No significant differences were observed in fasting serum glucose or body weight change. Incidents of level 1, level 2 (clinically significant), and level 3 (severe) hypoglycemia, as well as adverse and serious adverse events, were comparable between groups. Conclusion: Once-weekly insulin efsitora alfa demonstrates comparable efficacy and safety to daily basal insulin. However, further large-scale, long-term trials are warranted to confirm its durability, safety, and real-world effectiveness.